ABSTRACT
PURPOSE OF RESEARCH: Since, transient focal cerebral ischaemia exhibits detrimental effect not only during the course of ischaemia but also after the onset of reperfusion, the current study is focussed on identifying the appropriate therapeutic time point at which NG-nitro-l-arginine methyl ester (l-NAME) exerts better neuroprotection. PRINCIPAL RESULTS: Pre-ischaemic administration of l-NAME ameliorated neurological deficits much better than the during ischaemic and post-ischaemic groups. Pre-ischaemic l-NAME has also mitigated glutamate excitotoxicity, increased glutamine synthetase activity, ATP and NAD levels, decreased nitrate/nitrite content, down regulated TNF-α and upregulated IL-10 expressions and reduced the cerebral infarction significantly than the during ischaemic and post-ischaemic groups. MAJOR CONCLUSION: Current study revealed that l-NAME improved neurological deficit at the pre-ischaemic state in transient focal cerebral ischaemia and has also significantly ameliorated glutamate excitotoxicity. Though l-NAME showed neuroprotective effects when administered at during and post-ischaemia (during reperfusion), it exerts considerable neuroprotection when administered pre-ischaemically.
Subject(s)
Enzyme Inhibitors/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/psychology , NG-Nitroarginine Methyl Ester/therapeutic use , Nervous System Diseases/drug therapy , Adenosine Triphosphate/metabolism , Animals , Cerebral Infarction/drug therapy , Cerebral Infarction/psychology , Excitatory Amino Acid Antagonists/pharmacology , Glutamate-Ammonia Ligase/antagonists & inhibitors , Glutamic Acid/toxicity , Infarction, Middle Cerebral Artery/complications , Interleukin-10/metabolism , Male , NAD/metabolism , Nervous System Diseases/etiology , Nervous System Diseases/psychology , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Interactions between neurons and astrocytes play a critical role in the central nervous system homeostasis. Cyperus rotundus (family: Cyperaceae), a traditional Indian medicinal herb, used as nervine tonic and nootropic in the Ayurvedic system of medicine. The present study was undertaken to investigate the neuroprotective effect of total oligomeric flavonoids (TOFs), prepared from C. rotundus, in rat model of cerebral ischemia and reperfusion. Male Sprague Dawley rats (290-340g) were subjected to middle cerebral artery occlusion (MCAO) for 2h and reperfusion for 70h. Experimental animals were divided into four groups: Group I - sham operated (n=7); Group II - vehicle treated ischemic-reperfusion (IR) (n=9), and Group III and IV - TOFs treated (100 and 200mg/kg body weight, p.o., respectively; n=7 in each group). Vehicle or TOFs were pretreated for four days before the induction of ischemia and continued for next three days after the ischemia i.e. treatment was scheduled totally for a period of 7 days. MCAO surgery was performed on day 4, 1h after TOFs administration. Neuroprotective effect of TOFs was substantiated in terms of neurological deficits, excitotoxicity (glutamate, glutamine synthetase and Na(+)K(+)ATPase levels), oxidative stress (malondialdehyde, super oxide dismutase, and glutathione) and neurobehavioral functions in the experimental animals. TOFs decreased glutamate, glutamine synthetase (GS) and increased Na(+)K(+)ATPase activity in a dose dependent manner when compared to the IR rats. Treatment with TOFs significantly reduced the neurological deficits and reversed the anxiogenic behavior in rats. Further, it also significantly decreased MDA and increased superoxide dismutase (SOD) and glutathione content in brains of experimental rats. Histopathological examination using cresyl violet staining revealed the attenuation of neuronal loss by TOFs in stroke rats. The present study demonstrates the unswerving involvement of TOFs on ischemia-reperfusion triggered biochemical alterations in MCAO/R rats. Hence, TOFs might be an attractive candidate for further studies in the development of new drugs for cerebral stroke treatment.
